Management of dyslipidemia and hyperglycemia with a fixed-dose combination of sitagliptin and simvastatin

Figures & data

Table 1 Subject disposition in bioequivalence studies

Patient characteristics	100 mg sitagliptin/10 mg simvastatin	100 mg sitagliptin/80 mg simvastatin
Total patients randomized (n)	100	100
Male age (range) in years	41 (19–54)	61 (20–55)
Female age (range) in years	59 (18–53)	39 (20–55)
Completed (n)	93	98
Discontinued (n)	7	2
Clinical AEs (n)	0	0
Laboratory AEs (n)	0	0
Withdrew consent (n)	6	0
Protocol violation (n)	1	2

Abbreviation: AEs, adverse events.

Table 2 Statistical comparisons for the plasma PK parameters of sitagliptin, simvastatin, and simvastatin acid after a single-dose administration of FDC sitagliptin/simvastatin 100 mg/10 mg or 100 mg/80 mg tablet, or coadministration of corresponding doses of sitagliptin and simvastatin and individual tablets

PK parameter	100 mg/10 mg FDC/100 mg + 10 mg		100 mg/80 mg FDC/100 mg + 80 mg
	GMR	90% CI	GMR	90% CI
Sitagliptin
AUC0–∞ (nM*hr)	1.01	(0.99, 1.02)	0.99	(0.98, 1.00)
AUC0–last (nM*hr)	1.01	(1.00, 1.03)	0.99	(0.98, 1.00)
Cmax (nM)	1.03	(0.98, 1.07)	0.98	(0.94, 1.02)
Simvastatin
AUC0–last (nM*hr)	1.07	(0.99, 1.16)	0.99	(0.93, 1.05)
Cmax (nM)	1.13	(1.05, 1.21)	0.98	(0.92, 1.06)
Simvastatin acid
AUC0–last (nM*hr)	1.03	(0.96, 1.11)	0.93	(0.87, 0.98)
Cmax (nM)	1.04	(0.97, 1.12)	0.95	(0.88, 1.02)

Notes: The PK parameter values following a single-dose administration of study drug were compared using separate linear mixed-effect models appropriate for a two-period crossover design. The linear mixed-effect model contained factors for sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect. A log transformation was applied to the AUC and C_max data. Back-transformed summary statistics and inferential results were reported for PK parameter values. The 90% CIs were compared to the prespecified bounds of [0.80, 1.25].

* represents multiplication.

Abbreviations: AUC, area under the curve; C, concentration; CI, confidence interval; FDC, fixed-dose combination; GMR, geometric mean ratio; PK, pharmacokinetic.

Table 3 Statistical comparisons for the plasma PK parameters after administration of a single dose of digoxin 0.5 mg alone or sitagliptin 100 mg once daily and simvastatin 80 mg once daily for 9 days and a single dose of digoxin 0.5 mg on day 5 in healthy male and female subjects

PK parameter	(Digoxin + sitagliptin + simvastatin)/digoxin
	GMR	90% CI
AUC0–last (nM*hr)	1.26	(1.13, 1.41)
Cmax (nM)	1.41	(1.20, 1.66)

Notes: Back-transformed least-squares mean and CI from linear mixed-effects model performed on natural log-transformed values. The effects and variability due to subjects within sequence (a random effect) and sequence, period, and treatment (fixed effects), as well as the within-subject variability of the PK parameters were estimated using a mixed-effect analysis model appropriate for the two-period study design. A log transformation was applied to the digoxin AUC_0–last and C_max data. A 90% CI was constructed for the difference in least-squares means on the log scale. Exponentiation of the log scale 90% CI provided a 90% CI for the GMR ([digoxin + sitagliptin + simvastatin]/digoxin alone). The 90% CIs were compared to the prespecified bounds of [0.80, 1.25]. Summary statistics and comparisons were provided for C_max of digoxin.

Abbreviations: AUC, area under the curve; C, concentration; CI, confidence interval; GMR; geometric least-squares mean ratio ([digoxin + simvastatin + sitagliptin]/digoxin); PK, pharmacokinetic.